Persistent BMI profiles during adolescence: Associations with brain maturation and DNA methylation

Background Adolescence is a critical period for the emergence of obesity and disordered eating behaviours, yet the biological mechanisms underlying persistent differences in body mass index (BMI) development remain poorly understood. We investigated whether longitudinal BMI profiles are associated with behavioural, neurodevelopmental, and epigenetic variation during adolescence. Methods Participants from the IMAGEN cohort ( N = 1,296) were followed from ages 14 to 23 years. Latent profile analysis identified longitudinal BMI profiles. Disordered eating behaviours were repeatedly assessed across adolescence. Structural MRI acquired at ages 14 and 23 characterised longitudinal changes in grey matter volume (GMV), cortical thickness (CT), and sulcal depth (SD). Genome-wide DNA methylation was measured in whole blood at age 14. Epigenome-wide association studies (EWAS), functional enrichment analyses, and a DNA methylation-based BMI risk score (bmiMRS) were conducted. Results Two distinct BMI profiles were identified: a persistently overweight group and a persistently normal-weight group. Adolescents with persistent overweight showed progressively increasing BMI, greater eating-, weight-, and shape-related concerns, and more frequent dieting and binge-eating behaviours. They also exhibited atypical cortical maturation, characterised by attenuated cortical thinning, accelerated reductions in sulcal depth, and reduced grey matter volume loss within frontal and temporal association cortices. EWAS identified 29 BMI-associated CpGs (Bonferroni-corrected P < 1.3×10 -7 ), enriched for genes involved in adipogenesis, immune and inflammatory signalling, type 2 diabetes, and brain-related biological processes. The bmiMRS predicted BMI, cumulative BMI across adolescence, and membership of the persistently overweight group, and remained significantly associated with BMI in an independent cohort. Longitudinal analyses further suggested reciprocal associations between BMI and brain maturation, with higher BMI in early adolescence predicting subsequent regional GMV changes, whereas lower baseline cortical thickness predicted greater BMI increases independently of baseline BMI. Conclusions Persistent adolescent overweight is associated with distinct behavioural, neurodevelopmental, and peripheral epigenetic signatures. Integrating longitudinal neuroimaging and DNA methylation identifies molecular biomarkers and brain developmental features associated with sustained BMI elevation, providing a framework for earlier risk stratification and informing biologically grounded approaches to obesity prevention.

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Journal
Biological Psychiatry Global Open Science
Published
2026-09-01
DOI
https://doi.org/10.1016/j.bpsgos.2026.100820
Primary Topic
Genetic Syndromes and Imprinting
Type
article
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article

Persistent BMI profiles during adolescence: Associations with brain maturation and DNA methylation

Andreas Heinz, Sylvane Desrivières, Rüdiger Brühl, Tobias Banaschewski et al.
Biological Psychiatry Global Open Science
Genetic Syndromes and Imprinting
article

Persistent BMI profiles during adolescence: Associations with brain maturation and DNA methylation

Andreas Heinz, Sylvane Desrivières, Rüdiger Brühl, Tobias Banaschewski, Shitong Xiang, Antoine Grigis, Michael N. Smolka, Dimitri Papadopoulos Orfanos, Frauke Nees, Gareth J. Barker, Zuo Zhang, Ulrike Schmidt, Nathalie Holz, Hervé Lemaître, Sylvane Desrivières, Marie-Laure Paillère Martinot, Arun L.W. Bokde, Gunter Schumann, Eric Artiges, Nilakshi Vaidya, Rüdiger Brühl, Yan Sun, Sarah Hohmann, Tianye Jia, Robert Whelan, Henrik Walter, Tobias Banaschewski, Luise Poustka, Dimitri Papadopoulos Orfanos, Xinyang Yu, Penny Gowland, Hugh Garavan, Jean-Luc Martinot
article en

Abstract

Background Adolescence is a critical period for the emergence of obesity and disordered eating behaviours, yet the biological mechanisms underlying persistent differences in body mass index (BMI) development remain poorly understood. We investigated whether longitudinal BMI profiles are associated with behavioural, neurodevelopmental, and epigenetic variation during adolescence. Methods Participants from the IMAGEN cohort ( N = 1,296) were followed from ages 14 to 23 years. Latent profile analysis identified longitudinal BMI profiles. Disordered eating behaviours were repeatedly assessed across adolescence. Structural MRI acquired at ages 14 and 23 characterised longitudinal changes in grey matter volume (GMV), cortical thickness (CT), and sulcal depth (SD). Genome-wide DNA methylation was measured in whole blood at age 14. Epigenome-wide association studies (EWAS), functional enrichment analyses, and a DNA methylation-based BMI risk score (bmiMRS) were conducted. Results Two distinct BMI profiles were identified: a persistently overweight group and a persistently normal-weight group. Adolescents with persistent overweight showed progressively increasing BMI, greater eating-, weight-, and shape-related concerns, and more frequent dieting and binge-eating behaviours. They also exhibited atypical cortical maturation, characterised by attenuated cortical thinning, accelerated reductions in sulcal depth, and reduced grey matter volume loss within frontal and temporal association cortices. EWAS identified 29 BMI-associated CpGs (Bonferroni-corrected P < 1.3×10 -7 ), enriched for genes involved in adipogenesis, immune and inflammatory signalling, type 2 diabetes, and brain-related biological processes. The bmiMRS predicted BMI, cumulative BMI across adolescence, and membership of the persistently overweight group, and remained significantly associated with BMI in an independent cohort. Longitudinal analyses further suggested reciprocal associations between BMI and brain maturation, with higher BMI in early adolescence predicting subsequent regional GMV changes, whereas lower baseline cortical thickness predicted greater BMI increases independently of baseline BMI. Conclusions Persistent adolescent overweight is associated with distinct behavioural, neurodevelopmental, and peripheral epigenetic signatures. Integrating longitudinal neuroimaging and DNA methylation identifies molecular biomarkers and brain developmental features associated with sustained BMI elevation, providing a framework for earlier risk stratification and informing biologically grounded approaches to obesity prevention.

Biological Psychiatry Global Open Science
University of Vermont (US), Physikalisch-Technische Bundesanstalt (DE), Centre National de la Recherche Scientifique (FR), University of Nottingham (GB), Université de Bordeaux (FR), Inserm (FR), Universität Hamburg (DE), Wellcome Centre for Human Neuroimaging (GB), King's College London (GB), South London and Maudsley NHS Foundation Trust (GB), Peking University (CN), Université Paris Cité (FR), Trinity College Dublin (IE), Heidelberg University (DE), Fudan University (CN), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), University Hospital Heidelberg (DE), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Institut des Maladies Neurodégénératives (FR), Assistance Publique – Hôpitaux de Paris (FR), Central Institute of Mental Health (DE), University Medical Center Hamburg-Eppendorf (DE), Pitié-Salpêtrière Hospital (FR), CEA Paris-Saclay (FR), National Institutes for Food and Drug Control (CN), Global Brain Health Institute (US), University Medical Centre Mannheim (DE), Einstein Center for Neurosciences Berlin (DE), Shanghai Center for Brain Science and Brain-Inspired Technology (CN), Klinik und Poliklinik für Psychotherapie und Psychosomatik (DE), Freie Universität Berlin (DE), Technische Universität Dresden (DE), Charité - Universitätsmedizin Berlin (DE)
Fondation de l'Avenir pour la Recherche Médicale Appliquée, South London and Maudsley NHS Foundation Trust, UK Research and Innovation, National Institute for Health and Care Research, Department of Health and Social Care, King's College London, European Commission, Science Foundation Ireland, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, Bundesministerium für Bildung und Forschung, Fondation pour la Recherche Médicale, Fondation de France, China Scholarship Council, Fédération pour la Recherche sur le Cerveau, Mission Interministérielle de Lutte Contre les Drogues et les Conduites Addictives, National Institutes of Health, NIHR Maudsley Biomedical Research Centre, Medical Research Council
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